CuI‐catalyzed alkyne–azide cycloaddition provides 1,4‐disubstituted 1,2,3‐triazoles with such efficiency and scope that the transformation has been described as “click” chemistry. An overview of the mechanism of this remarkable reaction is presented as a means to explain the myriad of experimental results, particularly the various methods of catalyst generation, solvent and substrate effects, and choice of base or ligand. Both solution‐phase and solid‐phase results are comprehensively examined. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Reactions between aromatic thiols and conjugated cycloalkenones afford optically active 3-arylthiocycloalkanones, when chiral bases are used as catalysts. This paper reports a detailed investigation into the mechanism of this catalytic asymmetric synthesis. The reaction has been performed under a variety of conditions. Catalysts containing the 0-hydroxy amine moiety (cinchona and ephedra alkaloids) give higher reaction rates and higher enantiomeric excesses (ee's) (up to 75%) than catalysts without a hydroxyl function. Polar solvents, concentrated reaction solutions, and the presence of tetra-n-butylammonium salts lower the ee's substantially. Kinetic measurements on a quinine-catalyzed reaction in toluene solution point to a third-order reaction, first order in each of the reactants. Activation enthalpies are very low (~0 kcal/mol) and activation entropies highly negative (-62 cal/(mol K)). Models of the transition-state complexes of the thiol addition reactions are proposed, which account well for the experimental data on reaction rate, ee, and absolute configuration. The erythro cinchona and ephedra alkaloids catalyze the reaction via tight transition-state complexes, composed of three species: thiol, enone, and catalyst. Important for the geometry of these complexes are three stabilizing interactions: an electrostatic interaction between the thiol anion and the ammonium cation, a hydrogen bond between the catalyst hydroxyl group and the enone carbonyl group, and a dispersion interaction between the catalyst aromatic ring system and the thiol anion. Different steric conditions cause a free-energy difference between two possible orientations of the enone, resulting in formation of unequal amounts of R and S products. The threo cinchona alkaloids and the catalysts without a hydroxyl group lack at least one of the stabilizing interactions, leading to less structured transition states and consequently lower ee's. The suggestion is made that these mechanisms of asymmetric catalysis also hold for other reaction types, catalyzed by cinchona and ephedra alkaloids. The alkaloids having the erythro 0-hydroxy amine configuration can be viewed as bifunctional catalysts. The value of such chiral catalysts in catalytic asymmetric synthesis is discussed.

Since the discovery of Cu(I)-catalysed click chemistry, the field of peptidomimetics has expanded to include 1,4-connected 1,2,3-triazoles as useful peptide bond isosteres. Here, we report the synthesis of triazole-containing analogues of the naturally occurring tyrosinase inhibitor cyclo-[Pro-Val-Pro-Tyr] and show that the analogues retain enzyme inhibitory activity, demonstrating the effectiveness of a 1,4-connected 1,2,3-triazole as a trans peptide bond isostere.

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